WO2022170952A1 - Dérivé de pyridazinone polycyclique servant d'inhibiteur de sos1, son procédé de préparation et son utilisation - Google Patents

Dérivé de pyridazinone polycyclique servant d'inhibiteur de sos1, son procédé de préparation et son utilisation Download PDF

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WO2022170952A1
WO2022170952A1 PCT/CN2022/073466 CN2022073466W WO2022170952A1 WO 2022170952 A1 WO2022170952 A1 WO 2022170952A1 CN 2022073466 W CN2022073466 W CN 2022073466W WO 2022170952 A1 WO2022170952 A1 WO 2022170952A1
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membered
compound
heterocyclic group
mmol
general formula
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Chinese (zh)
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郑苏欣
谢成英
陆晓杰
郑明月
乔刚
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苏州阿尔脉生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of polycyclic pyridazinone derivatives, in particular to a polycyclic pyridazinone derivative as an SOS1 inhibitor, a preparation method and uses thereof.
  • the RAS family proteins belong to a small GTPase that includes three subfamilies, KRAS, NRAS, and HRAS.
  • the mutated RAS gene is an important oncogene, and RAS gene mutations are found in 20-30% of human tumors, especially pancreatic, colorectal, and lung cancers.
  • Various isoforms of RAS proteins have a balance between the activated state of GTP binding and the inactive state of GDP binding.
  • GTPase-activating proteins GAPs
  • GAPs can promote the conversion of GTP to GDP, thereby making RAS proteins inactive.
  • guanine nucleotide exchange factors can promote the release of GDP and the binding of GTP, thereby turning the RAS protein into the active state.
  • Activation of RAS protein can promote cell proliferation, apoptosis evasion and metabolic reorganization through the RAS-RAF-MEK-ERK and RAS-PI3K-PDK1-AKT signaling pathways, thereby promoting the occurrence and development of tumors.
  • SOS1 (son of sevenless 1) is a key guanine nucleotide exchange factor (GEF) that can bind to RAS protein, promote the binding of RAS protein to GTP, and turn RAS protein into an active state.
  • GEF guanine nucleotide exchange factor
  • Recent studies have found that SOS1 inhibitors not only inhibit the growth of RAS mutant cells, but also synergize with MEK inhibitors, resulting in significant inhibition of KRAS-driven tumors 1-2 .
  • the development of SOS1 inhibitors has become a research hotspot.
  • SOS1 inhibitors with different structural types, such as WO2018172250, WO2019201848, WO2018115380, WO2019122129, WO2020173935, WO2020180768 and WO2020180770, etc.
  • the purpose of the present invention is to provide a polycyclic pyridazinone derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof to screen out Compounds useful as SOS1 inhibitors with excellent properties in terms of efficacy, safety and selectivity.
  • Another object of the present invention is to provide a method for the preparation of the derivatives, their pharmaceutically acceptable salts, their tautomers or their stereoisomers.
  • the present invention provides a polycyclic pyridazinone derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, wherein the polycyclic pyridazinone derivative has The structure is shown in formula (I):
  • R 1 is selected from hydrogen or methyl
  • R 2 is selected from C 1 -C 3 alkyl, -OR 21 , halogen, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, 6-10 membered fused cycloalkyl, 7-10 membered bridge Cycloalkyl, 7-10-membered spirocycloalkyl, 4-7-membered heterocyclyl, 5-7-membered heterocycloalkenyl, 6-10-membered fused heterocyclyl, 7-10-membered bridged heterocyclyl , 7-10-membered spiro heterocyclyl, including 3-7-membered cycloalkyl, 5-7-membered cycloalkenyl, 6-10-membered fused cycloalkyl, 7-10-membered bridged cycloalkyl, 7- 10-membered spirocycloalkyl, 4-7-membered heterocyclyl, 5-7-membered heterocycloal
  • R 21 is selected from H, C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, wherein C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 4-7 membered cycloalkyl A membered heterocyclyl group is optionally substituted with 1-3 R 22 ;
  • R a and R b are independently selected from H, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, or substituted or unsubstituted 4-7 membered heterocycle group; here "substituted” means optionally substituted with 1-3 substituents selected from C 1 -C 3 alkyl, hydroxy, halogen, cyano, amino or alkoxy;
  • Q is selected from N or -CR 3 ;
  • R 3 is selected from H, C 1 -C 3 alkyl, halogen, cyano or -OR 21 ;
  • AR is selected from 6-10-membered aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-4 R c ;
  • R c is selected from H, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy-C 1 -C 4 alkyl, hydroxy-C 1 -C 4 haloalkyl, 3-6 membered cycloalkane base, 4-7 membered heterocyclyl, -OR 21 , -NR a R b , NR a R b -C 1 -C 4 alkyl, NR a R b -C 1 -C 4 haloalkyl, 6-10 membered aryl or 5-10-membered heteroaryl, wherein the 6-10-membered aryl or 5-10-membered heteroaryl is optionally substituted by 1-4 R d ;
  • R d is selected from H, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy-C 1 -C 4 alkyl, hydroxy-C 1 -C 4 haloalkyl, 3-6 membered cycloalkane base, 4-7 membered heterocyclyl, -OR 21 , -NR a R b , NR a R b -C 1 -C 4 alkyl, NR a R b -C 1 -C 4 haloalkyl;
  • heteroatoms in the heterocyclic group, heteroaryl group, heterocyclic alkenyl group, condensed heterocyclic group, bridged heterocyclic group and spiro heterocyclic group in the formula (I) are 1-7 and are selected from oxygen, nitrogen One or more of , sulfur and S(O)m, where m is 1 or 2.
  • the phenyl group is optionally substituted by 1-3 R c , when the number of the R c is 2-3, the R c can be the same or different;
  • the halogen atom therein is fluorine
  • the R a and R b may be the same or different.
  • R 2 is a 4-7-membered heterocyclic group optionally substituted by 1-3 R 22 , when the R 22 is 2-3, the R 22 same or different;
  • the heterocyclic group contains 1-2 heteroatoms
  • the heteroatom of the heterocyclic group is nitrogen and/or oxygen;
  • R 2 is a 4-7 membered heterocyclic group optionally substituted by 1-3 R 22 , when the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different;
  • R 2 is a 4-7-membered heterocyclic group optionally substituted by 1-3 R 22 , when the R 22 is 2-3, the R 22 same or different;
  • the heterocyclic group contains 1-2 heteroatoms
  • the heteroatom of the heterocyclic group is nitrogen and/or oxygen;
  • R 2 is a 4-7 membered heterocyclic group optionally substituted by 1-3 R 22 , when the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different;
  • R 21 is selected from unsubstituted C 1 -C 3 alkyl or unsubstituted 3-7 membered cycloalkyl.
  • the R a and R b are independently selected from H, substituted or unsubstituted C 1 -C 3 alkyl groups;
  • R 2 is a 4-7-membered heterocyclic group optionally substituted by 1-3 R 22
  • R 22 is 2-3, the R 22 are the same or different;
  • the heterocyclic group contains 1-2 heteroatoms
  • the heteroatom of the heterocyclic group is nitrogen and/or oxygen;
  • R 2 is a 4-7 membered heterocyclic group optionally substituted by 1-3 R 22 , when the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different;
  • R 21 is a 4-7 membered heterocyclic group
  • the R 21 is a 4-7 membered heterocyclyl
  • the 4-7 membered heterocyclyl is a 5-6 membered heterocyclyl
  • the heteroatom of the heterocyclic group is nitrogen and/or oxygen
  • the heterocyclic group contains 1-2 heteroatoms
  • R 21 is a 4-7 membered heterocyclic group
  • the heterocyclic group has two heteroatoms
  • the two heteroatoms are the same or different.
  • the R 21 is a 4-7 membered heterocyclyl
  • the R 21 is a 4-7 membered heterocyclyl
  • the 4-7 membered heterocyclyl is a 5-7 membered heterocyclyl
  • the heteroatom of the heterocyclic group is nitrogen and/or oxygen
  • the heterocyclic group contains two heteroatoms
  • R 21 when the R 21 is a 4-7 membered heterocyclic group, the two heteroatoms are the same or different;
  • the R d is selected from halogen, C 1 -C 4 alkyl, -NR a R b , -OR 21 , NR a R b -C 1 -C 4 alkyl;
  • the R a and R b are independently selected from H, substituted or unsubstituted C 1 -C 3 the alkyl group.
  • the R 21 is a 4-7 membered heterocyclyl
  • the R 21 is a 4-7 membered heterocyclyl
  • the 4-7 membered heterocyclyl is a 5-7 membered heterocyclyl
  • the heteroatom of the heterocyclic group is nitrogen and/or oxygen
  • the heterocyclic group contains two heteroatoms
  • R 21 when the R 21 is a 4-7 membered heterocyclic group, the two heteroatoms are the same or different;
  • the R d is selected from halogen, C 1 -C 4 alkyl, -NR a R b , -OR 21 , NR a R b -C 1 -C 4 alkyl;
  • R d is one NR a R b -C 1 -C 4 alkyl group
  • the R a and R b are independently selected from H, substituted or unsubstituted C 1 -C 3 alkyl.
  • polycyclic pyridazinone derivatives are selected from any one of the following structures:
  • Typical compounds of the present invention include, but are not limited to, the compounds in the following table:
  • the present invention provides a method for preparing a polycyclic pyridazinone derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof as described in the first aspect, wherein choose from one of the following two options:
  • the preparation method of the compound described in the general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • the aromatic compound of general formula (I-1) is subjected to metal-catalyzed cross-coupling to obtain the compound of general formula (I-2);
  • the compound of the general formula (I-2) is reacted under catalyst conditions to obtain a chiral sulfonimide compound of the general formula (I-3);
  • the compound of general formula (I-3) is reduced by a metal reducing agent to obtain a chiral compound of general formula (I-4);
  • the compound of general formula (I-4) is cleaved under acidic conditions by sulfonamide to obtain a chiral benzylamine compound of general formula (I-A);
  • X halogen preferably bromine.
  • the compound of the general formula (I-5) is subjected to a diazotization reaction to obtain the compound of the general formula (I-6);
  • the cyano group in the compound of the general formula (I-7) forms an amidine, and then the compound of the general formula (I-B) is obtained by transesterification with the ester group;
  • X and X are halogen, X is preferably bromine , and X is preferably iodine ;
  • the compound of the general formula (I-12) is subjected to halogenation to obtain the compound of the general formula (I-13);
  • the compound of the general formula (I-6) is subjected to substitution reaction to obtain the compound of the general formula (I-14);
  • the 4th step the compound of general formula (I-14) obtains the compound of general formula (I-15) through oxidation reaction;
  • the 6th step the compound of general formula (I-16) obtains the compound of general formula (I-7) through Abnormal Beckmann rearrangement reaction;
  • the seventh step in the compound of the general formula (I-7), the cyano group forms an amidine, and then with the ester group through transesterification to obtain the compound of the general formula (I-B);
  • X and X 1 are halogen, X is preferably chlorine, and X 1 is preferably iodine;
  • the compound of general formula (I-A) and the compound of general formula (I-B) are subjected to imine addition reaction to obtain the compound of general formula (I-8);
  • the compound of general formula (I-11) and the compound of general formula (I-25) are obtained by Buchwald/Suzuki reaction under basic conditions in the presence of a metal catalyst and a ligand to obtain the compound of general formula (I).
  • X and X 1 are halogen, X is preferably bromine and chlorine, X 1 is preferably iodine; W is H, Q, AR, R1 and R2 have the same defined ranges as above.
  • the preparation method of the compound described in the general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • the compound of the general formula (I-17) is subjected to a substitution reaction to obtain the compound of the general formula (I-18);
  • the compound of general formula (I-19) and the compound of general formula (I-26) obtain the compound of general formula (I-20) under basic conditions;
  • the 4th step the compound of general formula (I-20) obtains the compound of general formula (I-21) through oxidation reaction;
  • the 5th step the compound of general formula (I-21) obtains the compound of general formula (I-22) through Bouveault aldehyde synthesis reaction;
  • the sixth step the compound of general formula (I-22) and hydrazine hydrate obtain the compound of general formula (I-23) through addition cyclization reaction;
  • the compound of the general formula (I-23) is subjected to substitution reaction to obtain the compound of the general formula (I-24);
  • the ninth step the compound of general formula (I-Bb) and the compound of general formula (I-A) obtain the compound of general formula (I) through Buchwald reaction in the presence of a metal catalyst and a ligand under basic conditions;
  • X 2 , X 3 and X 4 are halogen, X 2 and X 3 are preferably bromine, X 4 is preferably iodine;
  • Q is selected from N or CR 3 ;
  • R 3 is selected from H, C 1 -C 3 alkyl, halogen, cyano or -OR 21 ;
  • R 1 is selected from hydrogen or methyl;
  • AR and R 2 have the same defined ranges as above.
  • the reagent for providing alkaline conditions is selected from organic bases or inorganic bases, and the organic bases are triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamine
  • the organic bases are triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamine
  • the inorganic bases are sodium hydride, potassium phosphate, sodium carbonate,
  • potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide sodium hydride, potassium phosphate, sodium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide;
  • the reagent for providing acidic conditions is one or more of hydrogen chloride, hydrogen chloride in 1,4-dioxane, hydrogen chloride in methanol, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid and phosphoric acid kind;
  • the metal catalyst is palladium/carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( Pd(dppf)Cl 2 ), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, bistriphenylphosphonium palladium dichloride (Pd(PPh) 3 ) one or more of Cl 2 ) and tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 );
  • the ligands are 2-dicyclohexylphosphine-2,6'-dimethoxybiphenyl (SPhos), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (XantPhos), 2- Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (DavePhos), 1, One or more of 1'-bis(diphenylphosphino)ferrocene (Dppf) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), preferably 1,1 '-Binaphthalene-2,2'-bisdiphenylphosphine (BINAP);
  • the reducing agent is one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum tetrahydrogen;
  • the oxidant is one or more of potassium permanganate, manganese dioxide, potassium dichromate, sodium dichromate and potassium osmate;
  • the above reaction is preferably carried out in a solvent, and the solvent used is N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, One or more of 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.
  • the solvent used is N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, One or more of 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the polycyclic pyridazinone derivative as described in the first aspect, a pharmaceutically acceptable salt thereof, a tautomer thereof or its stereoisomers;
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and/or excipient.
  • the present invention provides a polycyclic pyridazinone derivative as described in the first aspect, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof or as in the third aspect
  • a pharmaceutical composition in the preparation of a medicine for treating cancer or in the preparation of an SOS1 inhibitor;
  • the cancer is pancreatic cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, kidney cancer, gastric cancer or bile duct cancer.
  • the present invention provides a method for preventing and/or treating cancer, comprising administering to a human a therapeutically effective amount of the polycyclic pyridazinone derivative as described in the first aspect, which is pharmaceutically acceptable
  • the salt, its tautomer or its stereoisomer or the pharmaceutical composition as described in the third aspect is pharmaceutically acceptable.
  • Alkyl refers to a saturated aliphatic hydrocarbon group comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms , or a saturated linear or branched monovalent hydrocarbon group of 1-2 carbon atoms, wherein the alkyl group may be independently optionally substituted by one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1 ,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2 - Dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-di Methylbutyl etc. Alkyl groups can be optionally substituted or unsubstituted.
  • Alkenyl refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one CC is sp 2 double bond, wherein the alkenyl group can be independently optionally substituted by one or more substituents described in the present invention, specific examples of which include, but are not limited to, vinyl, allyl and alkene Butyl and so on. Alkenyl groups can be optionally substituted or unsubstituted.
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups can be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called spiro atom) with each other, and the ring contains one or more aromatic systems with double bonds but none of the rings have fully conjugated pi electrons.
  • spiro atom carbon atom
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spirocycloalkyl groups are divided into mono-spiro, double-spiro or poly-spirocycloalkyl groups, preferably mono-spiro and double-spirocycloalkyl groups, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan.
  • spirocycloalkyl include, but are not limited to:
  • “Fused cycloalkyl” refers to a 5- to 18-membered all-carbon polycyclic group containing two or more cyclic structures that share a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, But none of the rings have an aromatic system with fully conjugated pi electrons, preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl.
  • Non-limiting examples of "fused cycloalkyl” include, but are not limited to:
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more Aromatic systems in which multiple double bonds, but none of the rings have fully conjugated pi electrons, are preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • Non-limiting examples of "bridged cycloalkyl” include, but are not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring connected to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Heterocyclyl “heterocycle” or “heterocyclic” are used interchangeably in this application, and are used interchangeably in this application, and all refer to a saturated or partially unsaturated monocyclic ring containing 3-12 ring atoms , bicyclic or tricyclic non-aromatic heterocyclic groups, wherein at least one ring atom atom is a heteroatom, such as oxygen, nitrogen, sulfur atom and the like. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine base, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Piperazinyl.
  • the heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl.
  • Heterocyclyl groups can be optionally substituted or unsubstituted.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • spiroheterocyclyl include, but are not limited to:
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl include, but are not limited to:
  • bridged heterocyclyl include, but are not limited to:
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are C6 - C10 aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are phenyl groups.
  • Aryl groups can be substituted or unsubstituted.
  • the "aryl” can be fused with a heteroaryl, a heterocyclyl or a cycloalkyl, wherein an aryl ring is attached to the parent structure, non-limiting examples include but are not limited to:
  • Heteroaryl refers to an aromatic 5- to 6-membered monocyclic or 9- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and/or sulfur.
  • heteroaryl include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo-diazolyl Oxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindo
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:
  • Alkoxy refers to a group (alkyl-O-). Wherein, alkyl is as defined herein. Ci - C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Haloalkyl refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described herein.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.
  • Halogen means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Benzyl refers to -CH2 -phenyl.
  • Carboxyl refers to -C(O)OH.
  • Alcohol refers to -C(O) CH3 or Ac.
  • Carboxylate means -C(O)O(alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • the terms "subject,” “individual,” or “patient” are used interchangeably to refer to any animal, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates animals and humans.
  • the patient is a human.
  • the subject has experienced and/or displayed at least one symptom of the disease or disease to be treated and/or prevented.
  • the subject has been identified or diagnosed with cancer with a KRAS G12 or G13 mutation (eg, as determined by an FDA-approved regulatory agency, such as an FDA-approved assay or kit).
  • the subject has a tumor that is positive for a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12S mutation, a KRAS G12V mutation, a KRAS G12A mutation, a KRAS G13D mutation, or a KRAS G13C mutation (eg, as approved by a regulatory agency-approved test or kit determination).
  • the subject can be a person with a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12V mutation, a KRAS G12S mutation, a KRAS G12A mutation, a KRAS G13D mutation, or a KRAS G13C mutation (e.g., approved by an approved regulatory agency-such as an FDA-approved assay or reagent) Box) positive tumor patients.
  • a KRAS G12C mutation e.g., approved by an approved regulatory agency-such as an FDA-approved assay or reagent
  • the subject can be a subject whose tumor has a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12V mutation, a KRAS G12S mutation, a KRAS G12A mutation, a KRAS G13D mutation, or a KRAS G13C mutation (eg, the tumor was approved by an FDA-approved regulatory agency, kit or assay).
  • the subject is suspected of having a KRAS G12 or G13 gene-related cancer.
  • the subject has a clinical record indicating that the subject has a tumor with a KRAS G12C mutation (and optionally the clinical record indicating that the subject should be treated with any of the compositions provided herein).
  • the term "pediatric patient” as used herein refers to a patient under the age of 16 at the time of diagnosis or treatment.
  • the term "child” can also be divided into the following subcategories: neonatal (from birth to first month of life); infant (1 month to two years); child (2 to 12 years); adolescent (12 years) Age to 21 (until but not including 22nd birthday).
  • Berhman RE Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st ed. New York: McGrow-Hill, 2002; and Avery MD, 1st LR. Pediatric Medicine, 2nd ed. Baltimore: Williams &Wilkins; 1994.
  • an "effective amount" of a compound refers to an amount sufficient to negatively modulate or inhibit SOS 1 enzymatic activity.
  • a "therapeutically effective dose” of a compound refers to an amount sufficient to ameliorate or somehow reduce symptoms, halt or reverse disease progression, or negatively modulate or inhibit SOS 1 activity. This dose can be given as a single dose or in a regimen to be effective.
  • treating means in any way ameliorating or otherwise altering the symptoms or pathology of a patient's condition, disorder, or disease.
  • improving the symptoms of a particular disease by use of a particular compound or pharmaceutical composition means any reduction, whether permanent or temporary, attributable to or associated with use of the composition Sexual, permanent or temporary.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the part.
  • Diastereomers can be separated into individual diastereomers by methods such as chromatography, crystallization, distillation or sublimation on the basis of their physicochemical differences.
  • Enantiomers can be separated by converting a chiral mixture into a diastereomeric mixture by reaction with an appropriate optically active compound such as a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride , the diastereomers are separated, and the individual diastereomers are converted to the corresponding pure enantiomers.
  • the intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D, L or R, S are used to denote the absolute configuration of the chiral center of the molecule.
  • the prefixes d, l or (+), (-) are used to designate the sign of the plane-polarized light rotation of the compound, (-) or l means the compound is levorotatory, and the prefix (+) or d means the compound is dextrorotatory.
  • the atoms or groups of atoms of these stereoisomers are connected to each other in the same order, but their steric structures are different.
  • a specific stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during chemical reactions.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers, devoid of optical activity.
  • Tautomer or "tautomeric form” means that isomers of structures of different energies can be interconverted through a low energy barrier.
  • proton tautomers ie, prototropic tautomers
  • Valence (valence) tautomers include interconversions that recombine bond electrons.
  • the structural formulas described herein include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): such as R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers thereof are within the scope of the present invention.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention which are safe and effective when used in humans or animals.
  • the salts of the compounds can be obtained by using a sufficient amount of base or acid in neat solution or in a suitable inert solution to obtain the corresponding addition salts.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts, etc.
  • Pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts, and the inorganic and organic acids include Hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, rice butenedioic acid, Phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, and methanesulfonic acid, among others (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)).
  • the present invention provides an SOS1 inhibitor with a new structure, and the test results show that the polycyclic pyridazinone derivatives exhibit excellent SOS1 inhibitory activity, as well as excellent safety and selectivity, and can be used to prepare and treat cancer , especially for pancreatic, colorectal, lung, hepatocellular, renal, gastric and bile duct cancers.
  • Fig. 1 is a graph showing the effect of the compounds involved in the present invention on the KRAS/ERK1/2 signal transduction pathway of K-562 cells.
  • Figure 2 is a graph showing the effect of the compounds of the present invention on the KRAS/ERK1/2 signal transduction pathway of K-562 cells.
  • the mass spectrum was measured by LC/MS, and the ionization mode was ESI.
  • HPLC model Agilent 1260, Thermo Fisher U3000; Column model: Waters xbrige C18 (4.6*150mm, 3.5 ⁇ m); Mobile phase: A: ACN, B: Water (0.1% H 3 PO 4 ); Flow rate: 1.0mL/min; Gradient: 5%A for 1min, increase to 20%A within 4min, increase to 80%A within 8min, 80%A for 2min, back to 5%A within 0.1min; Wavelength: 220nm; Column oven: 35°C.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.2mm-0.3mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm.
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • reaction temperature is room temperature, which is 20°C-30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound or the developing solvent system of the thin layer chromatography method includes: A: Petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or basic reagent can also be added Adjustments such as acetic acid or triethylamine, etc.
  • TLC thin layer chromatography
  • reaction solution was cooled to room temperature, hydrochloric acid (15 mL, 3N) was added, stirred for 30 minutes, filtered through a pad of celite, the filtrate was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was filtered through silica gel Column chromatography gave the title compound IN-1b (1.25 g, 72% yield) as a yellow oil.
  • reaction solution was cooled to room temperature, poured into ice water (60 mL), extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound IN- 1c (1.01 g, 56% yield).
  • reaction solution was quenched by dropwise addition of water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound IN-1d (150 mg, yield 58) as a white solid %).
  • Methyl 2-amino-4-bromobenzoate IN-2a (2.0g, 8.70mmol) was dispersed in hydrochloric acid (20mL, 120mmol, 6M), cooled to about 0°C, and sodium nitrite (360mg, 5.22mmol) was added dropwise After the addition was completed, the reaction was continued for 1 hour, potassium iodide (1.4 g, 8.43 mmol) was added dropwise, the addition was completed, and the reaction was continued at room temperature for 2 hours. TLC detected that the reaction of the raw materials was basically complete.
  • reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-2b (2.1 g, yield 70) as a yellow oil. %).
  • the reaction solution was cooled to room temperature, filtered through celite, the filter cake was washed, the filtrate was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography The title compound IN-2c (1.2 g, 80% yield) was obtained as a white solid.
  • 2,2,6,6-Tetramethylpiperidine (11.2 g, 79.29 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to about -60°C under nitrogen protection, and n-butyllithium (31.7 mL, 79.25 mL) was added dropwise.
  • reaction solution was quenched by adding 1N hydrochloric acid, filtered, and the filter cake was washed and dried to obtain the title compound IN-3b (4.7 g, crude product) as a brown-yellow solid, which was directly used in the next step.
  • reaction solution was added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-3c (2.0 g, two-step yield) as a pale yellow solid. twenty one%).
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-3d (1.9 g, yield) as a pale yellow solid. rate 95%).
  • reaction solution was added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain the title compound IN-3e (1.3 g, collected) as a pale yellow oil (solidified on standing). rate 72%).
  • the seventh step 6-chloro-1-imino-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one IN-3h
  • Acetyl vanillin 1a (20.0 g, 103.0 mmol) and potassium bromide (39.96 g, 335.8 mmol) were dissolved in water (100 mL), cooled to 0 °C, and liquid bromine (18.27 g, 114.3 mmol) was added dropwise. After the addition was completed, the mixture was warmed to room temperature and stirred for 15 hours. TLC showed that a small amount of starting material remained. The reaction solution was filtered, and the filter cake was washed with water and dried to obtain the title compound 1b (aqueous crude product), which was directly used in the next step.
  • reaction solution was made weakly acidic by adding dilute hydrochloric acid (1N), extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 1h (1.4 g, three steps). yield 21%).
  • reaction solution was cooled to room temperature, filtered through a pad of celite, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 11 (50 mg, yield 20% for two steps).
  • the eleventh step 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl-6-( ((S)-Tetrahydrofuran-3-yl)oxy)phthalazin-1(2H)-one 1
  • 2-Piperazinone 7a (1.0 g, 9.99 mmol) was dissolved in ethyl acetate (20 mL), water (20 mL) and sodium carbonate (3.2 g, 30.19 mmol) were added, stirred at room temperature for 10 minutes, cooled to 0 °C, slowly Benzyl chloroformate (2.1 g, 12.31 mmol) was added dropwise, the liquid was stirred at room temperature after the addition, and the reaction was complete as detected by TLC.
  • reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 7b (2.3 g, yield 98%).
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound 11b (190 mg, crude product) as a yellow solid, which was directly used for Next step.
  • reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 12b (130 mg, yield 87%) as a yellow solid. ).
  • the first step 1- (2-Fluoro-3-(trifluoromethyl)phenethyl alcohol 14b
  • reaction solution was poured into saturated aqueous ammonium chloride solution and quenched, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 14b (11.1 g, crude product), which was directly used in the next step.
  • reaction solution was poured into vigorously stirred ice water, stirred continuously for 10 minutes, filtered, the filter cake was repeatedly washed with ethyl acetate, the filtrate was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 14d (11.0 g, crude) was used directly in the next step.
  • reaction solution was poured into saturated aqueous sodium bicarbonate solution and quenched, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 15b (8.1 g) as a yellow liquid. , the yield is 73%).
  • reaction solution was cooled to room temperature, diluted hydrochloric acid (14.4 mL, 72.0 mmol, 5 M) was added, and the mixture was stirred at room temperature for 1 hour. TLC showed that the reaction of the starting materials was complete.
  • the reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 15c (5.6 g, yield 83%) as a yellow liquid.
  • reaction solution was cooled to room temperature, poured into vigorously stirred ice water, stirred continuously for 10 minutes, filtered, the filter cake was repeatedly washed with ethyl acetate, the filtrate was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentration gave the title compound 16b as a yellow oil (9.0 g, crude), which was used directly in the next step.
  • reaction solution was poured into ice water and quenched, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound 16c (2.8 g, collected in two steps) as a brown oil. rate 21%).
  • reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound 17b (120 mg, yield 81%) as a yellow solid.
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 18d (37 mg, yield 21% for three steps) .
  • the fourth step 1- (((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(6-methyl-3,6-diazepine Bicyclo[3.1.1]heptan-3-yl)pyrido[3,4-d]pyridazin-4(3H)-one 18
  • the sixth step 1- (((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-((R)-2,4-dimethylpiperidine Azin-1-yl)pyrido[3,4-d]pyridazin-4(3H)-one 19
  • reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound 20b (5.0 g, yield 99.8%) as a yellow oil.
  • reaction solution was cooled to room temperature, the reaction solution was concentrated, the pH was adjusted to basic with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain colorless Liquid title compound 20d (3.1 g, 84% over two steps).
  • the sixth step 1- (((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-((S)-2,4-dimethylpiperidine Azin-1-yl)pyrido[3,4-d]pyridazin-4(3H)-one 20
  • reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound 21a (120 mg, yield 78%) as a yellow solid.
  • the third step 1- (((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-methyl-7-(1-methylpiperidine- 3-yl)pyrido[3,4-d]pyridazin-4-(3H)-one 22
  • O-formylboronic acid 23a (5.0 g, 33.35 mmol) was dissolved in methylamine ethanol solution (30 mL, 7 M), palladium/carbon (200 mg, 10%) was added, and the reaction was carried out at room temperature for 5 hours under a hydrogen atmosphere. TLC detected that the reaction of the raw materials was complete. The reaction solution was filtered through a pad of celite, the filter cake was washed, and the filtrate was concentrated to obtain the title compound 23b (5.3 g, crude product) as a pale yellow foamy solid, which was directly used in the next step.
  • reaction solution was added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, slurried with crude petroleum ether and ethyl acetate, filtered, and the filter cake was washed and dried to obtain the title compound 23c (7.4 g, two-step yield 84%) as a white solid.
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain the title compound 23f (800 mg, 64% yield in two steps) as a red oil. ).
  • the first step methyl(2-(5-((R)-1-((4-oxo-7-(((S)-tetrahydrofuran-3-yl)oxy)-3,4-dihydropyridine tert-Butyl [3,4-d]pyridazin-1-yl)amino)ethyl)thiophen-3-yl)benzyl)carbamate 24a
  • 3-Aminopyrrolidine-1-carboxylate tert-butyl ester 25a (800 mg, 4.30 mmol) was dispersed in methanol (10 mL), and aqueous formaldehyde (3.5 g, 43.12 mmol, 37%) and palladium/carbon (200 mg, 10%) were added ) and stirred overnight at room temperature under a hydrogen atmosphere.
  • the reaction solution was filtered through a pad of celite, the filter cake was washed with methanol several times, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 25b (900 mg, yield 98%) as a yellow liquid.
  • reaction solution was filtered while hot, the filter cake was washed with ethanol, the filtrate was concentrated, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to give the title compound 25 as a yellow solid ( 30 mg, yield 64%).
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 27b (115 mg, yield 87%) as a yellow solid ).
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 28a (282 mg, crude product) as a yellow solid, which was used directly with in the next step.
  • the third step 3-(1-(((R)-1-(3-acetylamino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-methyl-4-oxo-3 ,4-Dihydropyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate tert-butyl ester 28c
  • the sixth step 1- (((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-methyl-7-(1-methylpiperidine- 3-yl)pyrido[3,4-d]pyridazin-4(3H)-one 28
  • reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound 29a (260 mg, yield 70%) as a yellow solid.
  • the sixth step 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylpiperidin-3-yl)phthalein Azin-1(2H)-one 29
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 30a (240 mg, yield 99%).
  • the sixth step 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(1-methylpiperidine- 3-yl)phthalazin-1(2H)-one 30
  • reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound 31c-1 (75 mg, crude product) as a yellow solid, which was directly used in the next step.
  • reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound 31c-2 (75 mg, crude product) as a yellow solid, which was directly used in the next step.
  • the sixth step 1- (((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-((R)-1-methylpiperidine-3 -yl)pyrido[3,4-d]pyridazin-4(3H)-one 31-1&1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl yl)amino)-7-((S)-1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4(3H)-one 31-2
  • the human chronic myelogenous leukemia cell K-562 (CCL-243) used in the present invention was purchased from American Type Culture Collection (ATCC). Cells were grown in RPMI 1640 medium with 10% fetal bovine serum (FBS) and 1% dual antibodies at 37°C, 5% CO 2 .
  • FBS fetal bovine serum
  • Inhibition rate (control well OD570nm-OD690nm - administration well OD570nm-OD690nm )/control well OD570nm-OD690nm ⁇ 100%
  • IC50 values were calculated from compound concentrations and corresponding inhibition ratios using Graphpad prism 5.0 software. The test results are shown in Table 1.
  • Test Example 2 Effects of compounds on the phosphorylation level of KRAS downstream signaling molecule ERK1/2 in K-562 cells
  • Protein sample preparation collect the cell suspension, centrifuge at 500g for 5 minutes, discard the supernatant, wash 3 times with PBS, and use 1 ⁇ SDS gel loading buffer (50mM Tris-HCl (pH 6.8), 100mM DTT, 2% SDS, 10% glycerol, 0.1% bromophenol blue) 100 ⁇ L of lysed cells. Cell lysates were denatured by heating at 100°C for 10 minutes.
  • 1 ⁇ SDS gel loading buffer 50mM Tris-HCl (pH 6.8), 100mM DTT, 2% SDS, 10% glycerol, 0.1% bromophenol blue
  • Compound treatment Compounds with a final concentration of 400 times are prepared. For example, the final concentration of detection is 5uM, and the compounds are prepared to a concentration of 400 times, that is, 2 mM. The compound was serially diluted to the set number of concentration points using an automatic micropipette.
  • Transfer the compound to the 384-well reaction plate Use the ultrasonic nanoliter liquid processing system to transfer 50nL of the above diluted compounds from the Echo 384-well plate to the 384-well reaction plate, and transfer 100% of the 50nL for both the negative and positive controls. DMSO.
  • Transfer 2x detection solution Prepare 2x Anti-Tag1-Tb3+ and Anti-Tag2-XL665 solutions with the Detection Buffer provided in the kit, transfer 10ul to a 384-well reaction plate, centrifuge at 1000rpm for 1 minute, and incubate at room temperature 60 minutes.
  • Reading Read the data fluorescence signal value (Ex665/Em615) with a microplate reader Envision.
  • Inhibition rate (%) (maximum value-sample value)/(maximum value-minimum value) ⁇ 100%.
  • Compound number IC50 (nM) Compound number IC50 (nM) Compound number IC50 (nM) Compound number IC50 (nM) 3 15 4 13 5 7.6 10 16 12 9.7 13 7.8 14 18 15 14 16 8.0 17 7.7 18 12 19 6.8 20 6.0 twenty one 20 twenty two 29 twenty three 5.4 twenty four 18 25 11 26 30 28 12 29 14 30 twenty three
  • Test Example 4 Stability test of the compound on mouse and human liver microsomes
  • liver microsomes (20 mg protein/mL) from the -80°C refrigerator, pre-incubate on a 37°C water bath thermostatic shaker for 3 minutes, and thaw for use.
  • Control group (without ⁇ -NADPH): respectively take 25 ⁇ L of PB solution into 75 ⁇ L of the incubation system mixture described in (2), vortex for 30 s, mix well, the total reaction volume is 100 ⁇ L, and replicate. Put it into a 37°C water bath constant temperature shaker for incubation, and start timing. The sampling time points are 0min and 60min.
  • Sample group respectively add 25 ⁇ L of ⁇ -NADPH solution (4 mM) to 75 ⁇ L of the reaction system described in (2), vortex for 30 s, mix well, the total reaction volume is 100 ⁇ L, and replicate. Put it into a 37°C water bath constant temperature oscillator for incubation, and start timing. The sampling time points are 0min, 5min, 15min, 30min, and 60min.
  • CL int(liver) CL int(mic) ⁇ liver weight to body weight ratio ⁇ liver microsomal protein concentration per gram of liver
  • the present invention is to illustrate a polycyclic pyridazinone derivative of the present invention as an SOS1 inhibitor and its preparation method and application through the above-mentioned examples, but the present invention is not limited to the above-mentioned examples, that is, it is not limited to the above-mentioned examples. It means that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

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Abstract

L'invention concerne un dérivé de pyridazinone polycyclique servant d'inhibiteur de SOS1, son procédé de préparation et son utilisation. La structure du dérivé de pyridazinone polycyclique est telle que représentée par la formule (I), et présente un effet remarquable d'inhibition d'une voie de signalisation RAS et de traitement de cancers, tels que le cancer du pancréas, le cancer colorectal, le cancer du poumon, le carcinome hépatocellulaire, le cancer du rein, le cancer gastrique et le cancer des voies biliaires.
PCT/CN2022/073466 2021-02-09 2022-01-24 Dérivé de pyridazinone polycyclique servant d'inhibiteur de sos1, son procédé de préparation et son utilisation WO2022170952A1 (fr)

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CN115819251A (zh) * 2022-12-20 2023-03-21 沧州普瑞东方科技有限公司 一种(1r)-1-[3-(二氟甲基)-2-氟苯基]乙胺的制备方法
WO2023116902A1 (fr) * 2021-12-23 2023-06-29 北京望实智慧科技有限公司 Inhibiteur de sos1
WO2024074827A1 (fr) 2022-10-05 2024-04-11 Sevenless Therapeutics Limited Nouveaux traitements de la douleur
WO2024083257A1 (fr) * 2022-10-21 2024-04-25 上海领泰生物医药科技有限公司 Agent de dégradation de protéine sos1 et son utilisation

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CN1568187A (zh) * 2001-08-15 2005-01-19 Icos股份有限公司 2h－2,3－二氮杂萘－1－酮和其使用方法
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WO2024074827A1 (fr) 2022-10-05 2024-04-11 Sevenless Therapeutics Limited Nouveaux traitements de la douleur
WO2024083257A1 (fr) * 2022-10-21 2024-04-25 上海领泰生物医药科技有限公司 Agent de dégradation de protéine sos1 et son utilisation
CN115819251A (zh) * 2022-12-20 2023-03-21 沧州普瑞东方科技有限公司 一种(1r)-1-[3-(二氟甲基)-2-氟苯基]乙胺的制备方法
CN115819251B (zh) * 2022-12-20 2024-04-09 沧州普瑞东方科技有限公司 一种(1r)-1-[3-(二氟甲基)-2-氟苯基]乙胺的制备方法

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